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Microbiology and immunology > Tolerance, autoimmunity, and autoimmune diseases > Flashcards

Tolerance, autoimmunity, and autoimmune diseases Flashcards

1
Q

What are the two broad groups of autoimmune diseases?

A
  • Systemic diseases
  • Organ-specific diseases
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2
Q

What are the causes of autoimmune diseases?

A
  • Genetic predisposition (commonly involving HLA genes)
  • Environmental influences
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3
Q

Which organs are affected by SLE?

A
  • Joints: arthritis
  • Skin: butterfly rash on the face
  • Kidneys: inflammation
  • Blood cells
  • Heart: pericarditis
  • Lungs: pleurisy
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4
Q

Which genes are particularly important in the pathogenesis of SLE?

A
  • C1q, C2, and C4
  • FCGRIIB (for the IgG receptor FCγRIIb)
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5
Q

How does SLE develop, from an immune perspective?

A
  • B cells form autoantibodies nad present autoantigens for activation of autoreactive T cells
  • T cells participate through co-stimulator-mediated signaling pathways and secretion of cytokines
  • Innate immunity participates through a TLR on certain pDCs that can be activated by the autoimmune complex, inducing production of IFN-α and the formation of NETs
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6
Q

What are the phases in the pathogenesis of SLE?

A
  1. Loss of adaptive immune tolerance leads to an increase in autoreactive B cells
  2. Signals from self-antigens, TLR ligands, BAFF/APRIL, and T cell-derived cytokines promote the formation of germinal centers and production of autoantibodies
  3. Innate immune defects lead to increased availability of self-antigens, including increased NETosis, impaired clearance of apoptotic debris, and reduced phagocytosis
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7
Q

How is the immune system implicated in type 1 diabetes?

A
  • Decreased efficiency of negative selection of T cells, either due to altered tissue-specific antigen expression or due to TCR signaling, allows for the increased escape of pancreatic β cell-specific T cells
  • β cell-specific Foxp3+ Treg development may be suboptimal due to dysregulation of TCR signaling
  • β cell-specific T cells are stimulated in the pancreatic lymph nodes by APCs, leading to effector T cell formation. These effector T cells drive inflammation in the pancreatic islets
  • Ongoing islet inflammation also leads to generation of new autoantigens either directly in β cells or during antigen processing by APCs
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8
Q

What is Grave’s disease?

A

An autoimmune disease affecting the thyroid where autantibodies against the thyroid stimulating hormone (TSH) receptor act as agonists and induce hyperthyroidism and goiter

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9
Q

What are the symptoms of Grave’s disease?

A
  • Sweating
  • Exophthalmos
  • Goiter
  • Arrythmia and tachycardia
  • Nausea and diarrhea
  • Tremor
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10
Q

What are examples of autoantigens associated with SLE?

A
  • Nucleolin
  • Ku
  • Lamins
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11
Q

What are the types of self-tolerance?

A
  • Central tolerance: induced in immature self-reactive lymphocytes in the generative lymphoid organs, ensuring that the repertoire of mature lymphocytes is incapable of responding to self antigens
  • Peripheral: induced in mature lymphocytes in peripheral sites, preventing activation of self-reactive lymphocytes that managed to evade central tolerance measures
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12
Q

What are the mechanisms of central T cell tolerance?

A
  • Negative selection: deletion of T cells that react strongly to self-antigens by apoptosis
  • Development of these T cells into reuglatory T cells that do not perform immune-stimulating effector functions and promote peripheral tolerance
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13
Q

How are T cells exposed to a wide repertoire of antigens while in the thymus?

A

The thymic epithelium expresses many protein antigens that are typically present only in certain peripheral tissues by the function of autimmune regulator (AIRE) protein

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14
Q

What disease is associated with mutations in the AIRE gene?

A

Autoimmune polyendocrine syndrome type 1 (APS1)

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15
Q

What are the features of autoimmune polyendocrine syndrome type 1?

A

Antibody- and lymphocyte-mediated injury to multiple endocrine organs, including the parathyroids, adrenals, and pancreatic islets

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16
Q

What are the mechanisms of peripheral T cell tolerance?

A
  • Anergy: lack of costimulation leads to functional unresponsiveness
  • Suppression by regulatory T cells
  • Deletion by apoptosis
17
Q

How is anergy stimulated in T cells?

A
  • Exposure of mature CD4+ T cells to an antigen in the absence of costimulation or innate immune signals may make the cells incapable of responding
  • Full activation of T cells requires both antigen recognition by the TCR and recognition of costimulators, mainly B7, by CD28. Prolonged TCR stimulation without a costimulatory signal may lead to anergy
  • TCR-induced signal transduction is blocked in anergic cells by an unknown mechanism
  • When T cells recognize self antigens, they may engage inhibitory CD28 receptors, terminating T cell response
18
Q

What are the inhibitory signaling molecules of T cells?

A
  • CTLA-4: a CD28 receptor family member that binds to B7. This receptor blocks B7 molecules from binding to stimulatory receptors. Expressed on activated CD4+ cells
  • PD-1: has an ITIM (immunoreceptor tyrosine-based inhibition motif) that delivers inhibitory signals from self antigens and some viral antigens. Expressed on activated CD4+ and CD8+ cells
19
Q

How is apoptosis induced in T cells as part of peripheral tolerance?

A
  • Insufficiency of survival signals (namely IL-2) leads to apoptosis by the intrinsic pathway
  • Engagement of death receptors leads to apoptosis by the extrinsic pathway (Fas–FasL)
20
Q

How do regulatory T cells function in peripheral T cell tolerance?

A
  • Production of the immunosuppressive cytokines IL-10 and TGF-β
  • Reduced ability of APCs to stimulate T cells—the Treg cells bind B7 molecules on APCs using CTLA-4, reducing the costimulation of T cells
  • Consumption of IL-2, leading to apoptosis of T cells. This happens since Treg cells have high expression of IL-2 receptors
21
Q

What are the mechanisms of central B cell tolerance?

A
  • Receptor editing: moderate or strong binding of self-antigens in the bone marrow leads to reactivation of RAG1 and RAG2 and VJ recombination of the other Ig κ locus
  • Deletion by apoptosis of self-reactive B cells
  • Anergy: if developing b cells recognize self antigens weakly, the cells become functionally unresponsive and exit the bone marrow in this unresponsive state. Anergy is due to downregulation of BCR expression as well as a block in BCR signaling
22
Q

What are the mechanisms of peripheral B cell tolerance?

A
  • Anergy and deletion: some self-reactive B cells that are repeatedly stimulated by self antigens become unresponsive to further activation. These B cells may also be eliminated by Fas–FasL apoptosis (FasL on helper T cells, Fas on the B cell)
  • Engagement of inhibitory receptors lead to blockade of the effector functions of self-reactive B cells
23
Q

What are the mechanisms that lead to tolerance of commensal microbe antigens?

A
  • An abundance of IL-10–producing Treg cells
  • An unusual strain of dendritic cells in the intestines that respond to TLR engagement by being inhibited, not activated
24
Q

How are fetal antigens tolerated?

A

The generation of peripheral FoxP3+ Treg cells for paternal antigens

25
Q

What are the factors that lead to the pathogenesis of autoimmune diseases?

A
  • Inheritance of susceptibility genes
  • Environmental triggers, such as infections

One theory proposes that susceptibility genes interfere with self-tolerance and lead to generation of many self-reactive T cells and B cells. Environmental stimuli then cause cell and tissue injury, leading to increased presentation of self-antigens and generation of effector self-reactive T cells and autoantibodies

26
Q

Which genes contribute most to autoimmune diseases?

A

MHC genes

27
Q

Which autoimmune diseases are associated with certain MHC alleles?

A
  • Ankylosing spondylitis
  • Rheumatoid arthritis
  • Type 1 diabetes mellitus
  • Pemphigus vulgaris
28
Q

Which autoimmune diseases re associated with defects in the CTLA4 gene?

A
  • Autosomal dominant immune dysregulation syndrome
  • Type 1 diabetes mellitus
  • Rheumatoid arthritis
29
Q

Which autoimmune diseases are associated with defects in the FOXP3 gene?

A
  • Immune dysregulation
  • X-linked polyendocrinopathy and enteropathy (IPEX)
30
Q

Which autoimmune disease is associated with defects in the FAS gene?

A

Autoimmune lymphoproliferative syndrome (ALPS)

31
Q

Which autoimmune disease is associated with defects in the PTPN22 gene?

A

Rheumatoid arthritis

32
Q

Which autoimmune disease is associated with defects in the NOD2 gene?

A

Crohn disease

33
Q

Which autoimmune diseases are associated with defects in the IL23R gene?

A
  • Inflammatory bowel disease
  • Psoriasis
  • Ankylosing spondylitis
34
Q

Which autoimmune diseases are associated with defects in the CD25 gene?

A
  • Multiple sclerosis
  • Type 1 diabetes
35
Q

Defects in which gene are associated with multiple sclerosis?

A

CD25

36
Q

Defects in which genes are associated with type 1 diabetes?

A
  • CD25
  • MHC
  • CTLA4
37
Q

Defects in which genes are associated with inflammatory bowel disease?

A
  • NOD2 (Crohn disease)
  • IL23R
38
Q

Defects in which gene are associated with rheumatoid arthritis?

A
  • PTPN22
  • MHC
  • CTLA4
39
Q

How do infections contribute to autoimmune disease?

A
  • An infection in a tissue may induce a local innate immune response, leading to increased production of costimulators and cytokines (especially type I IFNs) by APCs, potentially activating self-reactive T cells
  • Some infectious microbes may produce peptide antigens that are similar to, and cross-react with, self antigens. Immune responses to these microbial peptides may result in autoimmune atacks (molecular mimicry)

Microbiology and immunology (33 decks)

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